This application claims the benefit of the filing date of German Patent Application Number 10063294.7-44, filed on Dec. 19, 2000, which application is hereby incorporated by reference.
One embodiment of the invention relates to substituted heterocyclo-norbomylamino derivatives having: a) an exo-configuration nitrogen and an endo-fused five-membered or six-membered ring of the formula (I), or b) an exo-configuration nitrogen and an exo-fused five-membered or six-membered ring of the formula (I a), 
wherein:
A is (C1-C4)-alkylene;
T is (C1-C4)-alkyl or H;
B is a saturated or unsaturated carbon five-membered or six-membered ring, which is unsubstituted or is substituted, having 1-3 substituents chosen from oxo, hydroxyl, (C1-C4)-alkoxy, and (C1-C4)-alkyl;
Het is a 5- or 6-membered, saturated or unsaturated, heterocycle that contains up to four identical or different heteroatoms chosen from O, S, N, and Se;
R is OH, F, Cl, Br, I, CN, NO2, phenyl, CO2R1, (C1-C4)-alkyl, (C1-C4)-alkoxy, amino, (C1-C4)-alkylamino, di(C1-C4)-alkylamino, or amino-(C1-C4)-alkyl,
wherein the alkyl radicals are unsubstituted or are completely or partly substituted by fluorine;
R1 is H or (C1-C4)-alkyl, which is unsubstituted or completely or partly substituted by fluorine;
n0, 1, 2, 3 or 4,
wherein, if n=2, 3 or 4, the substituents R are chosen independently of one another;
and their pharmaceutically tolerable salts or trifluoracetates.
Examples of compounds of the invention include those compounds having an exo-configuration nitrogen and endo-fused carbon five-membered or six-membered ring of the formula (I) and those compounds having an exo-configuration nitrogen and exo-fused carbon five-membered or six-membered ring of the formula (I a), wherein:
A is (C1-C2)-alkylene;
T is H or methyl;
B is a saturated or unsaturated carbon five-membered or six-membered ring;
Het is a 5- or 6-membered, saturated or unsaturated, heterocycle that contains up to three identical or different heteroatoms chosen from O, S, and N;
R is F, Cl, Br, iodine, amino, hydroxymethyl, OH, phenyl, CO2R1, (C1-C4)-alkyl, or (C1-C4)-alkoxy,
wherein the alkyl radicals are unsubstituted or completely or partly substituted by fluorine;
R1 is H or (C1-C4)-alkyl, wherein the alkyl radical is unsubstituted or completely or partly substituted by fluorine;
n0, 1, 2 or 3,
wherein, if n=2 or 3, the corresponding substituents R are chosen independently of one another;
and their pharmaceutically tolerable salts or trifluoracetates.
Further examples of compounds of the invention include those compounds having an exo-configuration nitrogen and endo-fused carbon five-membered or six-membered ring of the formula (I) and those compounds having an exo-configuration nitrogen and exo-fused carbon five-membered or six-membered ring of the formula (I a), wherein:
A is (C1-C2)-alkylene;
T is hydrogen;
B is a saturated or unsaturated carbon five-membered or six-membered ring;
Het is a 5- or 6-membered, saturated or unsaturated, heterocycle that contains up to two identical or different heteroatoms chosen from O, S, and N
R is F, Cl, Br, (C1-C4)-alkoxy or (C1-C4)-alkyl,
wherein the alkyl radicals are unsubstituted or completely or partly substituted by fluorine;
nis 0, 1 or 2, wherein, if n=2, the corresponding substituents R are chosen independently of one another;
and their pharmaceutically tolerable salts or trifluoracetates.
Even more examples of the compounds of the invention include those compounds having an exo-configuration nitrogen and endo-fused carbon five-membered or six-membered ring of the formula (I) and those compounds having an exo-configuration nitrogen and exo-fused carbon five-membered ring of the formula (I a) such as, for example:
exo/exo-(octahydro-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
(rac)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyrid in-3-ylmethylamine,
(+)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
(xe2x88x92)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
(rac)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyrazin-2-ylmethylamine,
(+)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyrazin-2-ylmethylamine,
(xe2x88x92)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyrazin-2-ylmethylamine,
exo/endo-(decahydro-1,4-methanonaphthalen-2-yl)pyrazin-2-ylmethyl-amine,
exo/endo-(octahydro-4,7-methanoinden-5-yl)thiophen-2-ylmethylamine,
exo/endo-(octahydro-4,7-methanoinden-5-yl)thiophen-3-ylmethylamine,
exo/endo-(3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
exo/endo-(3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
exo/endo-furan-3-ylmethyl-(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-furan-2-ylmethyl-(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-(decahydro-1,4-methanonaphthalen-2-yl)pyridin-3-ylmethylamine,
exo/endo-(octahydro-4,7-methanoinden-5-yl)-(1 H-pyrrol-2-ylmethyl)amine,
exo/endo-(octahydro-4,7-methanoinden-5-yl)-pyrimidin-5-ylmethylamine
and their pharmaceutically tolerable salts or trifluoracetates.
More examples of compounds of the invention include those compounds having an exo-configuration nitrogen and endo-fused carbon five-membered or six-membered ring of the formula (I) and those compounds having an exo-configuration nitrogen and exo-fused carbon five-membered ring of the formula (I a) such as, for example:
exo/exo-(octahydro-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
(rac)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
(+)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
(xe2x88x92)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
(rac)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyrazin-2-ylmethylamine,
(+)-exo/endo-(octahydro-4,7-methanoinden-5-yl)pyrazin-2-ylmethylamine,
exo/endo-(octahydro-4,7-methanoinden-5-yl)thiophen-2-ylmethylamine,
exo/endo-(3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-y l)pyrimidin-3-ylmethylamine,
exo/endo-(3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)pyridin-3-ylmethylamine,
exo/endo-(decahydro-1,4-methanonaphthalen-2-yl)pyridin-3-ylmethylamine,
exo/endo-(octahydro-4,7-methanoinden-5-yl)-(1H-pyrrol-2-ylmethyl)amine,
exo/endo-(octahydro-4,7-methanoinden-5-yl)-pyrimidin-5-ylmethylamine
and their pharmaceutically tolerable salts or trifluoracetates.
Suitable acid addition salts of the compounds of the invention include salts of pharmacologically tolerable acids, for example halides (such as hydrochlorides), lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates, adipates, fumarates, gluconates, glutamates, glycerophosphates, maleates, and pamoates. This group also exemplifies some of the physiologically acceptable anions, in addition to trifluoracetates.
If a compound of the formula (I) or (I a) contains one or more asymmetric centers, these centers can have either the S or the R configuration. The compounds can be present as optical isomers, diastereomers, racemates, or mixtures thereof. However, the amino substituent on the norbornyl system must be exo and the ring endo- or exo-fused
The alkyl or alkylene radicals mentioned can be either straight-chain or branched.
Suitable heterocycles include, inter alia: 
Another embodiment of the invention relates to a process for the preparation of the compounds of the formula (I) or (I a), which comprises
a) reacting a compound of the formula (II) or (II a) 
with a compound of the formula (III) 
in the presence of suitable reductants and possibly also Lewis acids directly to give compounds of the formula (I) or (I a),
wherein T, B, Het and Rn have the meanings indicated above; independently of one another Axe2x80x2 corresponds to a bond or (C1-C3)-alkyl and Axe2x80x3 corresponds to H or (C1-C3)-alkyl; and Axe2x80x2 and Axe2x80x3, together with the carbon atom of the carbonyl group, represent as many carbon atoms as A represents in formula (I) or (I a);
or
b) isolating an intermediate of the formula (IV) or (IV a), formed from reacting compounds of the formulae (II), or (II a), with a compound of formula (III), and then converting the intermediate of the formula (IV) or (IV a) into the compounds of the formula (I) or (I a) by using suitable reductants, 
wherein T# is a free electron pair or (C1-C4)-alkyl. When T# is (C1-C4)-alkyl, an iminium ion is formed, to which a counterion is assigned, such as, for example, chloride or tosylate,
or
c) reacting a compound of the formula (II) or (II a) with an alkylating agent of the formula (V), 
wherein U is a nucleophilically substitutable group, such as for example a halogen, alkylsulfonates, or arylsulfonates, including Cl, Br, I, mesylate, or tosylate, and the other radicals are defined as described above. Here, the carbon atom to which U is bonded corresponds to the carbon atom of the carbonyl group of the compound of formula (III),
or
d) reducing carboxamides of the formula (VI) or (VI a) to the corresponding amines, 
wherein A* corresponds to a bond or (C1-C3)-alkyl and the other radicals are defined as described above,
or
e) alkylating compounds of the formula (I) or (I a) in which T corresponds to hydrogen, using alkylating agents of the formula (VII),
T*xe2x80x94Uxe2x80x83xe2x80x83VII 
wherein T* is(C1-C4)-alkyl and U has the meaning described above, so that tertiary amines result from this reaction;
or
f) reacting a dicyclopentadienylplatinum complex of the formula (VIII) 
with amines of the formula (IX), 
and subsequently reducing the intermediate formed to compounds of the formula (I) or (I a) (J. K. Stille and D. B. Fox, JACS 92:1274 (1970)),
wherein T, Rn and Het have the meanings indicated above; independently of one another, Axe2x80x2 corresponds to a bond or (C1-C3)-alkyl and Axe2x80x3 to H or (C1-C3)-alkyl; and Axe2x80x2 and Axe2x80x3, together with the carbon atom to which the nitrogen atom is bonded, represent as many carbon atoms as A represents in formula (I).
The compounds of formula (I) or (I a) may be optionally converted into the pharmaceutically tolerable salt or trifluoroacetate.
It has already been proposed that phenylalkyl-substituted norbornylamino derivatives are effective inhibitors of the sodium-proton exchanger, subtype 3 (NHE3). In this case, it appears that, of several stereoisomers, the compounds having an exo/endo-configuration octahydro-4,7-methanoinden-5-ylamine unit, wherein the nitrogen is exo and the five-membered ring is endo-fused, are active NHE3 inhibitors. Substances having an exo/exo-configuration octahydro-4,7-methanoinden-5-ylamine unit likewise showed marked NHE3-inhibiting action, while the corresponding endo/endo and endo/exo derivatives were markedly less active on the NHE3 (German published application 199 60 204 A1-HMR 99/L 073).
Surprisingly, it has now been found that the aromatic moiety of the phenylalkyl substituents can be substituted by heteroaromatic rings producing NHE3-inhibiting activity.
The relatively long-known inhibitors of the sodium/proton exchanger, subtype 3 disclosed in EP-A 825 178 (HOE 96/F226) represent relatively polar structures and correspond to the acylguanidine type of compounds (J.-R. Schwark et al. Eur. J. Physiol (1998) 436:797). In contrast, the compounds according to the invention are surprisingly lipophilic substances that are not of the acylguanidine type. See also the proposed compounds of the phenyalkyl norbornylamine type (DE 199 60 204.2-HMR 99/L 073). Squalamine and the above phenylalkyl norbornylamino derivatives are only the fourth substance class of NHE3 inhibitors known hitherto (M. Donowitz et al., Am. J. Physiol. 276 (Cell Physiol. 45): C136-C144). Additionally, squalamine does not achieve its maximum potency immediately, but only after approximately one hour. Compared with the above acylguanidines, the compounds of the invention are distinguished by their superior ability to cross the membrane and, compared with squalamine, by a more rapid onset of action.
NHE3 is found in the body of various species, mostly in the bile, the intestine, and in the kidney (Larry Fliegel et al., Biochem. Cell. Biol. 76: 735-741 (1998)), but can also be detected in the brain (E. Ma et al., Neuroscience 79: 591-603).
The compounds of the formula (I) or (I a) according to the invention are suitable for use as antihypertensives for the treatment of primary and secondary hypertension.
Moreover, these compounds, on their own or in combination with NHE inhibitors of other subtype specificity, can protect acutely or chronically oxygen-deficiently supplied organs by reducing or preventing ischemically induced damage. Thus, the compounds of the invention are suitable as pharmaceuticals, in the treatment of acute or chronic kidney failure and during surgical interventions such as in organ transplantation of the kidney and liver, where the compounds can be used both for the protection of the organs in the donor before and during removal and for the protection of removed organs, (for example during treatment with or storage in physiological bath fluids, and during transfer to the recipient""s body). Ischemically induced damage to the intestine can also be avoided.
Corresponding to the protective action against ischemically induced damage, the compounds of the invention are also potentially suitable as pharmaceuticals for the treatment of ischemia of the nervous system, including the CNS, where they are suitable, for example, for the treatment of stroke or cerebral odema. Moreover, the compounds of the formula (I) or (I a) according to the invention are likewise suitable for the treatment of forms of shock, such as, for example, allergenic, cardiogenic, hypovolemic, and bacterial shock.
Furthermore, the compounds of the invention induce an improvement in the respiratory drive and are therefore used for the treatment of respiratory conditions in the following clinical conditions and diseases: disturbed central respiratory drive (e.g. central sleep apnea, sudden infant death, post operative hypoxia), muscular-related respiratory disorders, respiratory disorders after long-term ventilation, respiratory disorders during adaptation in a high mountain area, obstructive and mixed forms of sleep apnea, acute and chronic lung diseases with hypoxia and hypocapnia.
The compounds of the invention additionally increase the muscle tone of the upper airways, so that snoring is suppressed.
A combination of an NHE inhibitor with a carboanhydrase inhibitor, (e.g. acetazolamide) where the latter produces metabolic acidosis and thereby even increases the respiratory activity, proves to be advantageous as a result of increased activity and decreased use of active compound.
It has been shown that the compounds according to the invention have a mild laxative action and accordingly can be used advantageously as laxatives or, in the case of threatening intestinal blockage, for the prevention of ischemic damage that accompanies blockages in the intestinal region.
Furthermore, the use of the compounds of the formula (I) or (I a) according to the invention makes it possible to prevent gallstone formation.
The compounds of the formula (I) or (I a) according to the invention additionally show an action against ectoparasites.
Moreover, the compounds of the formula (I) or (I a) according to the invention can exert an inhibitory action on the proliferation of cells, for example fibroblast cell proliferation and the proliferation of the smooth vascular muscle cells. The compounds of the formula (I) or (I a) are therefore suitable as valuable therapeutics for diseases in which cell proliferation is a primary or secondary cause, and can therefore be used as antiatherosclerotics, as agents against diabetic late complications, cancers, fibrotic disorders (such as, for example, pulmonary fibrosis, liver fibrosis, or kidney fibrosis), endothelial dysfunction, and organ hypotrophy and hyperplasia, such as, for example, prostate hyperplasia or prostate hypertrophy.
The compounds according to the invention are effective inhibitors of the cellular sodium/proton antiporter, which is raised in numerous disorders (essential hypertension, atherosclerosis, diabetes etc.) even in those cells that are easily accessible to measurement, such as, for example, erythrocytes, platelets or leukocytes. The compounds according to the invention are therefore suitable as outstanding and simple scientific tools, for example in their use as diagnostics for the determination and differentiation of certain forms of hypertension, athererosclerosis, diabetes, proliferative disorders, etc. Moreover, the compounds of the formula (I) or (I a) are suitable for preventive therapy to prevent the development of high blood pressure, for example of essential hypertension.
It has moreover been found that NHE inhibitors exhibit a favorable influence on the serum lipoproteins. It is generally recognized that for the formation of artereosclerotic vascular changes, for example in coronary heart disease, excessively high blood lipid values, xe2x80x98hyperlipoprotanemiasxe2x80x99, are an important risk factor. The lowering of increased serum lipoproteins is therefore of extreme importance for the prophylaxis and the regression of atherosclerotic changes. The compounds according to the invention can therefore be used for the prophylaxis and regression of atherosclerotic changes by excluding a causal risk factor. With this protection of the vessels against the syndrome of endothelial dysfunction, compounds of the formula (I) or (I a) are valuable pharmaceuticals for the prevention and treatment of coronary vascular spasms, athereogenesis and athereosclerosis, left-ventricular hypertrophy and dilated cardiomyopathy, and thrombotic disorders.
The compounds mentioned are therefore advantageously used for the production of a medicament for the prevention and treatment of sleep apneas and muscular-related respiratory disorders; for the production of a medicament for the prevention and treatment of snoring, for the production of a medicament for lowering the blood pressure, for the production of a medicament having laxative action for the prevention and treatment of intestinal blockages; for the production of a medicament for the prevention and treatment of disorders that are induced by ischemia and reperfusion of central and peripheral organs, such as acute kidney failure, stroke, endogenous states of shock, intestinal disorders, etc; for the production of a medicament for the treatment of hypercholesterolemia; for the production of a medicament for the prevention of atherogenesis and of athereosclerosis; for the production of a medicament for the prevention and treatment of diseases which are induced by raised cholesterol levels; for the production of a medicament for the prevention and treatment of diseases which are induced by endothelial dysfunction; for the production of a medicament for the treatment of attack by ectoparasites; for the production of a medicament for the treatment of the diseases mentioned in combination with blood pressure-lowering substances, for example angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists. A combination of an NHE inhibitor of the formula (I) or (I a) with an active compound lowering the blood lipid level, such as an HMG-CoA reductase inhibitor (e.g. Lovastatin or Pravastatin) proves to be a favorable combination having intensified action and decreased use of active substance. In this case, the HMG-CoA reductase inhibitor produces a hypolipodemic effect and thereby increases the hypolipodemic properties of the NHE inhibitor of the formula (I) or (I a).
The administration of sodium/proton exchange inhibitors of the formula (I) or (I a) as novel pharmaceuticals for lowering raised blood lipid levels, and the combination of sodium/proton exchange inhibitors with pharmaceuticals having a blood pressure-lowering and/or hypolipodemic action is claimed.
Pharmaceuticals containing a compound of formula (I) or (I a) can be administered orally, parenterally, intravenously, rectally, or by inhalation. The method of administration depends on the particular clinical picture of the disorder. The compounds (I) or (I a) can be used on their own or together with pharmaceutical excipients, namely both in veterinary and in human medicine.
The person skilled in the art is familiar on the basis of his/her expert knowledge with excipients that are suitable for the desired pharmaceutical formulation. In addition to solvents, gel formers, suppository bases, tablet excipients, and other active compound carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corregents, preservatives, solubilizers, and/or colorants.
For a form suitable for oral administration, the active compounds are mixed with the additives suitable therefor, including excipients, stabilizers, or inert diluents, and brought by means of the customary methods into the suitable administration forms, including tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic, or oily solutions. Inert carriers that can be used include, for example, gum arabic, magnesia, magnesium carbonates, potassium phosphates, lactose, glucose, starch, or cornstarch. Preparation can be carried out either as dry or as moist granules. Possible oily excipients or solvents include, for example, vegetable or animal oils, such as, for example, sunflower oil or cod-liver oils.
For subcutaneous or intravenous administration, the active compounds are brought into solution, suspension, or emulsion, if desired with the substances customary therefor such as, for example, solubilizers, emulsifiers, or further excipients. Suitable solvents include, for example, water, physiological saline solution, or alcohols (e.g. ethanol, propanol, glycerol), and sugar solutions such, for example, as glucose or mannitol solutions, or alternatively a mixture of the different solvents mentioned.
Pharmaceutical formulations suitable for administration in the form of aerosols or sprays include, for example, solutions, suspensions, or emulsions of the active compound of the formula (I) or (I a) in a pharmaceutically innocuous solvent, such as, ethanol or water, or a mixture of such solvents.
If required, the formulation can also contain other pharmaceutical excipients such as, for example, surfactants, emulsifiers and stabilizers, and a propellant. Such a preparation may contain the active compound in a concentration of approximately 0.1 to 10% by weight, and sometimes approximately 0.3 to 3% by weight.
The dose of the active compound of the formula (I) or (Ia) to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; on the nature and severity of the disease to be treated; and on the sex, age, weight, and individual responsiveness of the mammal to be treated.
On average, the daily dose of a compound of the formula (I) or (Ia) in the case of a patient weighing approximately 75 kg may be at least 0.001 mg/kg, sometimes 1-10 mg/kg, and at most 100 mg/kg, of bodyweight. In acute episodes of the diseases, even higher and more frequent doses may also be necessary, e.g. up to 4 individual doses per day, for instance in the case of i.v. administration, for example in the case of an infarct patient in the intensive care unit, up to 200 mg per day may be necessary.
Abbreviations used: